Colony-stimulating factor-1 receptor (FMS, also known as CSF-1R) is a homodimeric, class III receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1 or macrophage colony-stimulating factor, M-CSF) that is encoded by the FMS proto-oncogene and has been the focus of recent reviews [Nat. Rev. Immunol. 2008, 8, 533.]. CSF-1 regulates the survival, proliferation, differentiation, and function of the macrophage lineage, including monocytes, tissue macrophages, dendritic cells, microglia, and osteoclasts [Trends Cell Biol. 2004, 14, 628-638.]. These mononuclear phagocytes act as a defence against invading pathogens by maintaining tissue homeostasis. CSF-1 exists in 3 major isoforms, namely, a secreted glycoprotein and a secreted proteoglycan, both of which circulate throughout the body, and a cell surface protein, which is involved in local regulation of target cells.
The class III receptor tyrosine kinases (RTKs), which include c-FMS, c-Kit, Flt-3, and PDGFR, are characterized by an extracellular ligand-binding domain, a single transmembrane domain (TM), a juxtamembrane domain (JM), two intracellular kinase domains (TK1 and TK2) divided by a kinase insert domain (KI), and a C-terminal domain.
Binding of CSF-1 to the extracellular domain of FMS stabilizes receptor dimerization, induces trans-autophosphorylation of the intracellular FMS domain, and activates downstream cytoplasmic signaling, which leads to differentiation and activation of macrophage lineage cells.
Small molecule inhibitors of the FMS active site block receptor autophosphorylation and subsequently block the signals that control the survival, expression, proliferation, and differentiation of macrophages. Evidence linking macrophage numbers to several diseases, including cancer and inflammatory disease, has led to extensive efforts in developing small molecule inhibitors of FMS. In studies, high macrophage levels in target tissues have been correlated with disease severity in RA [Ann. Rheum. Dis. 2005, 64, 834-838] and immune nephritis [Nephrol. Dial. Transplant. 2001, 16, 1638-1647] and poor survivability and tumor progression [J. Clin. Oncol. 2005, 23, 953-964. Cancer Res. 2006, 66, 605-612] in some cancers. Consequently, regulation of macrophage numbers may be the key role of CSF-1 function.
The colony-stimulating factors (CSFs) are a group of hematopoietic cell growth factors that include M-CSF and granulocyte colony-stimulating factor (G-CSF), both of which are relatively lineage-specific, and granulocyte/macrophage CSF (GM-CSF), which functions at earlier stages of cell lineage by regulating hematopoietic progenitors [1]. Recently, a new ligand for FMS has been identified, interleukin-34 (IL-34), which functions as a specific and independent ligand of FMS, stimulates FMS dependent phosphorylation of extracellular signal-regulated kinase-1 and -2 (ERK1/2), and promotes the formation of the colony-forming unit-macrophage (CFU-M) in human bone marrow cultures [Science 2008, 320, 807-811].
FMS is a critical player in the CSF-1 pathway and has emerged as a viable target for regulating macrophage levels in multiple diseases including cancer, inflammation, and autoimmunity. Therefore, the identification of novel and selective small molecule CSF-1 antagonists has become the focus of extensive competitive research efforts By regulating the development and activation of mononuclear phagocytes, CSF-1 plays a key role in the innate immune response to viral, bacterial, and fungal infections and increases the efficiency of vaccination. CSF-1 is also involved in promoting and sustaining inflammation in several diseases. Early evidence that CSF-1 depletion has a therapeutic benefit in autoimmune and inflammatory diseases was observed in the collagen-induced arthritis (CIA) mouse model. CSF-1-deficient mice were resistant to the development of arthritis despite a normal immune response to type II collagen[23]. Indeed, increased levels of CSF-1, like that found in the synovial fluid of RA patients, demonstrate a strong correlation with disease severity in conditions such as RA and immune nephritis. The proinflammatory cytokines interleukin-1β (IL-1β) and TNF-α that stimulate the production of these synovial macrophages also play a contributing role. In the CIA model, both monoclonal antibodies and small-molecule inhibitors of CSF-1 have shown efficacy in decreasing macrophage numbers in joints and slowing the overall progression of disease.